As used herein, the term “erectile dysfunction” (ED) refers to certain disorders of the cavernous tissue of the penis and the associated facia which produce the inability to attain a sexually functional erection, priapism, the persistent and often painful erection of the penis, and Peyronie's syndrome, a condition characterized by fibrosis of the cavernous tissue and associated painful and distorted erection of the penis. Erectile dysfunction affects a substantial number of patients. ED can result from any of numerous physiological or psychological factors which cause the blood flow to and from the penis to remain in balance thereby preventing retention of sufficient blood to cause an erection. As used herein, the term “erectile dysfunction” is used in its broadest sense as the inability to attain a sexually functional erection when desired.
Millions of men suffer from ED and have sought an effective and pain free cure that can be sustained and presents no dangerous side effects. To that end, several therapies have become available, including penile implants, penile injection of vasoactive compounds, vacuum—constriction devices, PDE5 inhibiting pills and topical and intra-urethral vasoactive compounds. The penile implant was the first effective therapeutic method used for the treatment of ED (see Wilson S K and Delk J R I I. Int J Imp Res. 4:S101-07, 2000). Over the years, implant designs have generally remained as either semi-rigid or inflatable. Additionally, due to the fact that they require surgery and have led to complications such as infection, rejection and mechanical failure, implants have usually remained as the method of last resort for most men. As a result, despite their effectiveness, only about 10-12,000 are placed each year in the United States. Therefore most men suffering from ED have searched for other alternatives to treat their condition.
The next effective therapy method used for the treatment of ED was penile injection with vasoactive drugs. Although this approach has been successful for many men, the drop out rate has proven to be high because most men are reluctant to self-inject the drugs and many have experienced pain and scarring as a result of the injections. Furthermore, the long-term stability of the compounds used for this method requires that they be refrigerated or maintained under special conditions for transport by the patients. Several patents, including U.S. Pat. Nos. 3,927,197 and 5,741,523, have been issued for the development of chemical formulations utilizing vasoactive compounds to reduce pain and improve stability.
Another method for treating ED, which has proven effective for many users, is vacuum erection devices with constriction rings. Some current systems, including U.S. Pat. No. 4,995,381, have achieved FDA approval because they have been engineered with safety features such as pressure governors, quick release valves and safe constriction rings. Like the use of vasoactive gels, these systems can also be used in combination with other therapies. However, the use of vacuum devices with constriction rings is unattractive to many prospective users because the mechanical apparatus can be intimidating and the method is not conducive to spontaneous use.
The availability of phosphodiesterase type 5 (PDE5) inhibitors has made a great impact on the treatment of ED. These drugs, available in tablet form, have been taken by millions of men and they have also been used for men with comorbidities. However, these tablets present some major negative drawbacks. For instance, PDE5 inhibitors cannot be used for men using nitroglycerine products or that have a history of retinal problems. In addition, PDE5 inhibitors have also been shown to cause headaches and nasal congestion. For these reasons, there are many dropouts associated with these medications; leading to a search for alternative treatments for ED (see Rupesh R et al. J Androl. 26:757-60, 2005).
Recently, the use of topical and intra-urethral products has received attention because they are readily transportable, minimally invasive and have the potential for use with combination therapy. Several patents have been granted to inventors who described topical products and delivery systems related to the treatment of ED. For example, U.S. Pat. No. 4,801,587 describes a gel containing a combination of vasodilators. The product is placed topically on the penis, and then into the urethra using a catheter. The urethra was chosen for application because, unlike the penile skin, the urethral mucosa is not keratinized and contains specific receptor sites and many other drug products have been placed there for absorption (see Holstein A F et al. Cell Tiss. Res. 264:23-32, 1991, Pudney J and Anderson D J. Amer. J. Path. 147:155-165, 1995 and DeBenedictis T J et al. J Urol. 118:767-769, 1977). U.S. Pat. No. 5,242,391 discloses an invention of a coated pellet containing Prostaglandin Subgroup 1 (PGE1) and a dispenser for insertion into the urethra. This product has been sold and used in clinical practice under the trade name MUSE. Although this product has had positive responses among a variety of ED patients, many reports also suggest that users have experienced pain from insertion of the dispenser and a throbbing pain as a direct result of the PGE1 product in 35-60% of the cases (see Linet et al. NEJM 334:873, 1996).
For this reason, alternative solutions of ED treatment using pre-mixed PGE1 based compositions have been sought. For example, U.S. Pat. No. 6,323,241 discloses an invention of a PGE1 gel with several chemical ingredients including penetration enhancers and a buffer system to maintain a final pH in the range of 3-7.4. While this product was reported to have a 73.1% satisfaction rate, 14.6% of the patients complained of pain (see Zhao D et al. Zhonghua Nan Ke Xue 9:48-50, 2003).
It has been suggested that there is a relation to the pain caused by topical methods and the PH level of the pre-mixed product. Some studies have shown that higher pH levels have reduced the amount of pain associated with the use of PGE1 (see Moriel E Z and Rajfer J. J Urol. 149 1299-300, 1993). However, it is difficult to maintain the pH level of pre-mixed PGE1 based products because the ingredients may precipitate upon standing at a higher pH. Further disadvantages of pre-mixed PGE1 compositions include a short shelf life that requires products to be used immediately to achieve the desired results and the requirement for special additives that adds to the cost and complexity of the system.
All of the therapies mentioned above have been used for the definitive treatment of ED, but each has been shown to have limitations. As a result, many men are reluctant to try some of these methods and those who have used one or more of these methods have discontinued use because of side effects or a failure to consistently achieve desired results. Therefore, there is an on-going need for improved methods of treatment for men with ED. In accordance, the present system represents a simplified approach to the storage, mixing and intra meatal delivery of a vasoactive gel.